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Abstract

Prediction of prostate cancer clinical outcome remains a major challenge after diagnosis. Several high throughput approaches were applied to analyze the genome abnormalities of prostate cancer. To evaluate whether copy number variation (CNV) of genomes in prostate cancer (T), benign prostate tissues adjacent to tumor (AT) and blood of prostate cancer patients predicts biochemical (PSA) relapse and the kinetics of relapse, 241 samples were analyzed through Affymetrix SNP 6.0 chips. Using gene specific CNV from T, the genome model correctly predicted 73% cases for relapse and 75% for short PSADT. The gene specific CNV model from AT correctly predicted 67% cases for relapse and 77% for short PSADT. Using median size of CNV from blood, the genome model correctly predicted 81% for relapse and 69% for short PSADT. To analyze epigenome abnormalities of prostate cancer, genome wide methylation analyses were performed using both array and whole genome methylation sequencing approaches for 91 human prostate specimens. A gene methylation prediction model was shown to predict prostate cancer relapse with sensitivity of 80.0% and specificity of 85.0%. Through whole genome methylation sequencing, we found both intragene and promoter CpG islands contributed to the suppression of RNA transcription. Most of the differential methylation between T and AT occurred in regions outside the CpG islands. Our analysis indicates that genome or epigenome abnormalities of benign or malignant tissues are predictive of clinical outcome of a malignancy.

Biography

Jianhua Luo been studying molecular pathology related to human malignancies in the last 23 years. Currently, he is a Professor of Pathology and Director of High Throughput Genome Center at University of Pittsburgh. In the last 13 years, Dr. Luo has been largely focusing on genetic and molecular mechanism of human prostate and hepatocellular carcinomas. In this period, his group has identified and characterized several genes that are related to prostate cancer and hepatocellular carcinoma, including SAPC, myopodin, CSR1, GPx3, ITGA7, MCM7, MT1h and GPC3. He has characterized several signaling pathways that play critical role in prostate cancer development, including Myopodin-ILK-MCM7 inhibitory signaling, myopodin-zyxin motility inhibition pathway, CSR1-CPSF3 and CSR1-XIAP apoptotic pathways, MT1h-EHMT1 egigenomic signaling, ITGA7-HtrA2 tumor suppression pathway, GPx3-PIG3 cell death pathway, and AR-MCM7 oncogenic pathway. He proposed prostate cancer field effect in 2002. He is one of the pioneers in utilizing high throughput gene expression and genome analyses to analyze field effects in prostate cancer and liver cancer. He is also the first in using methylation array to analyze prostate cancer. Recently, Dr. Luo?s group found that patterns of copy number variants of certain specific genome loci, are predictive of prostate cancer clinical outcomes, regardless tissue origin. Overall, these findings advance our understanding on how cancer develops and behaves, and lay down the foundation for better future diagnosis and treatment of human malignancies.